Human aging is generally accompanied by a gradual decline in various physiological functions, which in some people results in physical impairments, and ultimately may cause disabilities which worsen the quality of life and limit independence. Normal aging is also frequently associated with reduced circulating levels of growth hormone (GH), insulin-like growth factor-I (IGF-I, and sex steroid hormones; decreased muscle mass and strength; and increased total and intra-abdominal fat. Treatment with recombinant human GH (rhGH) or sex steroids can improve body composition in some older persons, yet the effects of such hormonal treatment (singly or in combination) on various physiological functions remain to be defined. We hypothesize that age-related decreases in GH, IGF-I and sex steroids separately and interactively contribute to diminished skeletal muscle mass and strength, increased body fat, and reduced aerobic capacity in elderly women and men; and that restitution of normal GH, IGF-I and sex steroid status by combined hormone therapy will exert additive or synergistic effects to increase muscle mass and strength, decrease body fat, and increase aerobic capacity. Thus, we are now conducting a placebo-controlled, double-masked study in a group of healthy, ambulatory, community-dwelling women and men beyond 65 years of age, with low IGF-I and sex steroid levels, to determine whether 6-months of administration of rhGH alone, sex steroids hormones alone (estrogen/progestin in women and testosterone in men), or combined rhGH plus sex steroids will increase or improve skeletal muscle mass, strength, and total body protein synthesis; decrease total and abdominal fat; and improve aerobic capacity and cardiovascular function, as well as selected endocrine, metabolic, immunological, dermatological, and psychobehavioral functions. We are also using PCR techniques to assess mRNAs for GH and IGF-I receptors, IGF-I, and IGF-I binding proteins in skeletal muscle biopsy specimens; and the relationships between the latter molecular events and certain physiological outcome variables. Should the current study reveal beneficial effects of hormone replacement, then we plan to conduct certain targeted, longer-term investigations to examine the interactions of similar hormone treatments with other interventions (e.g. exercise conditioning), and their effects on functional status measurements, in selected elderly populations.